Project Summary/Abstract The mucosal system of the female reproductive tract (FRT) is multifactorial, combining epithelial and mucus barriers, a highly specialized immunology, the microbiome, and hormonal fluctuations to protect this complex and essential organ from attack by pathogen?s such as HIV. Perturbation of any of the components of this system has the potential to decrease barrier function while potentially increasing a woman?s vulnerability to HIV sexual acquisition. Recent studies have revealed that an increase in the presence of multiple (more than 3) pro-inflammatory cytokines are a strong signature of increased HIV acquisition in women. This increased inflammatory environment is consistent with the dysfunction of normal mucosal barrier function. A number of factors have been implicated in this inflammatory state including hormones, the microbiome, and epithelial barrier disruption. However, the origin of these inflammatory cytokines and the mechanism of how they are related to increased HIV acquisition is not understood. To advance HIV prevention science, we need a better understanding of the FRT mucosal system. In this project we will examine hysterectomy derived cervical tissues and mucus donated by high-risk populations in Nairobi, Kenya to gain insight into the changes in the mucosal system that alters epithelial and mucus barrier function. The increased Inflammatory cytokine production can directly or indirectly influence tissue resident HIV target cells to increase the probability of sexual transmission. Our hypothesis is that target cells become more susceptible to HIV infection by infiltrating into the squamous epithelium of the FRT in response to the increased inflammatory cytokines. We will also examine how antibodies can potentially enhance the mucus barrier function potentially revealing a novel strategy for HIV vaccine development.